The invention is directed to the fields of pharmaceutics, pharmaceutical nanotechnology and pharmacology and relates to a system for the delivery of biologically active compounds, including medicinal products, into an organism and to a method for the preparation of said system, wherein said invention can be used in medicine.
Systems for the delivery of biologically active compounds, including medicinal products, into an organism in the form of phospholipid nanoparticles with particle size of 10-30 nm, comprising phosphatidylcholine from plants and maltose (1), are known in the art.
Systems for the delivery of biologically active compounds, including medicinal products, into an organism as a combination thereof with a polymer excipient are known in the art. Nanoparticle-containing medications may be prepared by introducing a biologically active substance, or a medicinal product, during or after obtaining a polymeric dispersion. The active ingredients are dissolved, captured, or adsorbed on the surface of nanoparticles. A combination of said mechanisms is also possible [2]. However, polymer nanoparticles may have substantial disadvantages. With the exception of alkyl cyanoacrylate, most monomers form slowly biodegradable or non-biodegradable polymers. In addition, the molecular weight of the polymeric material cannot be fully controlled. The residues in the polymerization medium may be toxic, which would require a follow-up purification of the colloid system. Often, during polymerization, monomer molecules can react with medicinal product molecules, which results in the deactivation or destruction thereof [3].
A nanodiamond-based system for the delivery of medicinal products, with particle size of 5 nm, comprising an adsorbed antibiotic Doxorubicin and hydrated water molecules is known in the art [4].
A nanodiamond-based system for the delivery of medicinal products, comprising carboxylated nanodiamond particles with particle size of 3-5 nm, wherein CH20(CH2)6NH2-groups with the antitumor diterpenoid paclitaxel covalently bonded thereto attach to the surface of said nanodiamond in the course of several chemical transformations is known in the art [5].
Fluorine-modified nanodiamond particles with particle size of 2-10 nm containing up to 5% of fluorine at are known in the art [6]. The obtained nanodiamond that is modified with fluorine is used to prepare conjugants with such substances as alkyl lithium compounds, diamines, and amino acids. Said conjugants can be used as bonding agents in polymer compositions, abrasives and coatings, adsorbents, biosensors, and nanoelectromechanical systems.
A method for improving the efficacy of medicinal products by chemically (covalently) bonding the molecules of medicinal products to nanodiamond particles, 10 nm in size, via fluorine atoms and/or hydroxyl groups on the surface thereof is known in the art [7].
Fluorine atoms in an organic substance increase its toxicity; in particular, such substance can damage the nervous system, lungs, and liver. Despite being chemically inert, even the perfluorinated organic compounds alter the microsomal system of the xenobiotic biotransformation indicators (foreign bodies) in the liver [8]. Thus, the fluorine atoms covalently bound to the C60 fullerene molecule, which is the closest nanostructured carbon analog of the nanodiamond, have been shown to increase its overall toxicity 2.4-5 times [9].
Thus, preparation of nanodiamond particles with no fluorine atom content, which could be used as a system for the delivery of biologically active substances into an organism, present an important and practically relevant task for medical and pharmaceutical industries.
A method to increase the efficacy of medicinal products by chemical (covalent) bonding of the medicinal product molecules with nanodiamond particles 10 nm in size via amino or acyl chloride groups on the surface thereof is known in the art [10].
Nanodiamond particles modified with chlorine, wherein the chlorine content is up to 12%, wherein the particle size in the suspension one month post synthesis is 70 nm, and 9 months post synthesis is 180 nm, respectively, are known in the art [11]. These particles are larger in size than the optimally sized particles required for medical use. In addition, this work was not able to produce the highest chlorine content on the nanodiamond's surface, which, in turn, would, subsequently, not yield a maximum content of the medicinal product on the nanodiamond's surface, which invariably reduces the efficacy of the delivery system. Although the inventors [11] point out that testing of nanodiamond samples, modified with chlorine, by the X-ray photoelectron spectroscopy (XPE) method confirm the bonding of chlorine atoms with the surface carbon atoms, the supporting data are not listed. In addition, the analysis of the IR-spectra presented in the article, which the inventors themselves conducted, does not confirm the presence of such chemical bonds. Purportedly, this is because the chlorine atoms are bound to the nanodiamond's surface by way of adsorption and not by covalent bonds. Consequently, medicinal products do not create sufficiently strong chemical bonds with said surface of the nanodiamond, and the system becomes inefficient.
The following method for the preparation of said nanodiamond's particles, modified with chlorine, and the embodiment thereof are also known in the art [11]. Chlorination of the nanodiamond's particles is conducted by liquid-phase chlorination of the reduced nanodiamond in a CC14 solution saturated with chlorine at room temperature with constant stirring for 72 hours and exposure to visible light. Upon chlorination, the nanodiamond particles are washed with dry CC14, centrifuged, and the residue is dried for 5-6 hours under 13-26 Pa pressure at 70-80° C.
In the embodiment of said method, the particles of nanodiamond modified with chlorine are prepared in the CC14 plasma for 4 hrs. [11].
The inventors [11] concluded that the bond they created between the chlorine atoms and the nanodiamond is less stable in air (due to the purported adsorption nature of the bond) than the bond between the nanodiamond and the fluorine atoms. In addition, the highest possible number of fluorine atoms bound to the surface of the nanodiamond is higher than that of chlorine atoms, which makes the chlorinated nanodiamond particles less favorable for the participation in the future covalent bonding reactions of chemical compounds as compared to the fluorinated nanodiamond particles.
Thus, the task of creating nanodiamond particles that do not contain fluorine and can effectively form covalent bonds with various biologically active compounds, comprising medicinal products, has been only partially solved. Moreover, a complete substitution of the chlorine atoms (covalently bound to the nanodiamond's surface with molecules of biologically active compounds) creates perspective systems for the delivery of biologically active compounds containing no halogen atoms on their surface, which inhibits uncontrollably increased toxic effects. This requirement is of utmost importance for any medicinal and medical products used in the medical and pharmaceutical industry.